Table of Contents
- Network Refinement Process
- Pediatric, Adolescent, Maternal HIV Research
- Interoperable Sites to Address Infectious Disease Outbreaks
- Funding, Partnerships, and Strategy
- Data Sharing and Interoperability
- HIV Vaccine Research
- Co-Infections and Co-Morbidities
- Implementation Science
- HIV Therapeutics
- HIV Prevention
- Clinical Trials Units and Clinical Research Sites
Is there a deadline for submitting comments and questions?
The deadline for feedback is November 30, 2017. In the coming months, NIAID will be hosting a series of webinars to discuss, build, and refine the research agenda. In addition, there will be many opportunities for formal and informal discussions, including at network meetings.
What advice would you give the current clinical research sites to begin preparing for these anticipated changes?
It is very important for the site and unit investigators and research community to provide input on what scientific questions need to be addressed for 2020 and beyond. Also, we encourage the sites to stay connected to DAIDS and the current networks and to remain active in the process.
When in 2019 is the due date for the network awards and the CTU awards?
As of now, we have not finalized the due dates for the funding opportunity announcements. We plan to share our proposed dates at the upcoming advisory committee meetings.
Please elaborate on the planned integration of pediatric, adolescent, and maternal research questions within the three high-priority focus areas (non-vaccine prevention, vaccines, and therapeutics).
Many of the research questions for prevention, vaccines, and therapeutics that need to be addressed in 2020 and beyond are relevant to both adolescents and adults. For example, research on HIV cure and TB will be relevant across the age spectrum. It is important to distinguish which questions are unique to distinct age groups. We must also take into account expected research progress and developments between now and the renewal date. By answering those questions, we can begin to determine the size, scope, and direction of the research agenda for each age group. We are seeking input from you to determine the most relevant and impactful questions in these defined areas of research and age groups, which will help focus the future research agenda.
Is the current structure of having a separate network for pediatric, adolescent, and maternal research expected to continue beyond 2020?
We are taking into account the scientific questions that need to be addressed in 2020 and beyond. Currently assessments of those questions indicate that a network dedicated to pediatric, adolescent and maternal research may not be the most strategic method of delivering the innovative, efficient results needed to turn the corner on the HIV/AIDS pandemic. Moving forward, NIH is seeking to create an integrated network model that will cover adults, pediatrics, adolescents, and pregnant women in the areas of vaccines, prevention, and therapeutics.
You mentioned that pediatric vaccines were part of the agenda. Can you elaborate on how you see work on pediatric vaccines intersecting with the Vaccine and Treatment Evaluation Units?
As one example, within NIH and NIAID, there are several groups working to develop and evaluate RSV vaccines. NIAID has used the HIV/AIDS clinical research sites and the Vaccine and Treatment Evaluation Units (VTEUs) to evaluate RSV vaccines through the IMPAACT network. We have worked to pair the best sites—those affiliated with either IMPAACT or VTEUs—with the appropriate research protocols. This will ensure that the sites selected for a particular protocol (e.g., the next generation of RSV vaccines) will be robust, effective enrollers.
Historically, research on adolescents, pregnant women, and HIV-infected children has not been prioritized within the more adult areas of focused treatment or vaccines. How will NIAID ensure that prioritization is given to the meaningful inclusion of these populations in NIAID-supported research?
The high-priority questions that need to be addressed in HIV-infected children, adolescents and pregnant women will ultimately drive the research agenda. For example, the single most important thing we can accomplish for HIV-infected children is to evaluate the best drugs that are currently licensed and used in adults so they can be given safely and easily to infants and children. While some trials are underway now, others still require partnerships with industry to move forward. This needs to be a top priority as we approach 2020. With respect to adolescents and prevention, we need to consider enrolling this population in the clinical trials of injectable cabotegravir where it is legal and ethical to do so. Some networks, such as the Microbicides Trials Network, have already begun pursuing enrollment of young children in research.
How do you envision the pediatric-focused agenda on women, infants, children and youth to function efficiently and attain priority status across the proposed three networks?
Investigating HIV prevention and treatment options for women and adolescents is a top priority for NIAID as we think about positioning the HIV scientific agenda through 2027. Today, we have answered many of the big questions in HIV/AIDS pediatric research, particularly in preventing perinatal HIV transmission and treating pediatric HIV/AIDS. However, there are still some areas where it is essential to have a strong emphasis in pediatrics. For example, the adolescent agenda needs to focus on improving treatment and prevention strategies. Developing prevention tools that work for young people – particularly young women – will be pivotal in reducing new infections. We need to also focus on cure and co-infection research in young children. These are areas that are cross-cutting for the future treatment and prevention and treatment networks. These are pressing scientific questions, which will be delineated in the RFAs, will set the agenda for future research. As we move forward, we need to recognize where we are today and where we are going in the future.
Are non-HIV vaccines in pediatrics still a priority for the networks? Will this fall into the vaccine network?
Yes, non-HIV vaccine research will still be a priority and this area of research. It is important that we have a designated home for this type of work, and we are interested in evaluating pediatric vaccines that are relevant to HIV-infected youth and at-risk individuals.
There is a history of difficulty for combined networks to balance the scientific priorities between the pediatric and adult populations. What mechanisms would you build into the RFA to assure appropriate consideration of both populations’ research questions?
The pediatric research agenda, particularly related to adolescents, is of critical importance. We are currently in the process of refining the areas for emphasis and once they are finalized, we will clearly define them in the RFA and expect the networks to address these areas appropriately in their proposed research plans. We also need to make sure that within a given leadership group, there is appropriate balance in priorities and coverage for appropriate populations. NIH will facilitate and monitor the implementation of the research agendas across the lifespan. There may be instances when a set of research activities are being driven primarily by a group focused on a particular population (e.g., pediatrics) or outcomes (e.g., drug licensure studies for hepatitis C drugs in pregnant women). There will be opportunities to set limits and balance the priorities at the leadership level to ensure the networks can carry out the research plans for all the respective populations.
You appear to be specifically disbanding networks that focus on women and children. This historically has not worked for HIV networks. Can you give an example where such an integration has been successful?
Developing prevention and treatment tools for young women and children is inarguably one of the highest priorities for NIH HIV research and will continue to be paramount in the next iteration of the clinical research enterprise. We have made tremendous progress in HIV/AIDS pediatric research, particularly in perinatal transmission of HIV. The Promoting Maternal-Infant Survival Everywhere (PROMISE) study has addressed a number of important questions in the HIV/AIDS pediatric research agenda and moving forward, we need to refocus and integrate pediatric research into the prevention, vaccine and therapeutics research agendas. It is a logical next step as we consider adolescents and prevention research and cure, vaccine, prevention and co-infection research in young pediatric populations. We need to focus on the research agenda and build a network structure that can successfully carry out the research activities. Because this area of research is so important to NIAID and to ending the HIV/AIDS pandemic, strong emphasis will be placed on developing an inclusive, strategic research agenda and ensuring that the networks develop research to address the prevention and treatment advances needed to improve the health of these populations. To this end we will ensure that we have the clinical site capacity and leadership at the CTU and CRS level to help develop and then oversee and implement this important research agenda.
Can you expand on the role of the networks in non-HIV diseases such as Ebola and Zika?
The NIAID HIV/AIDS clinical trials networks have played an important role in addressing non-HIV infectious diseases. For example, during the pandemic flu outbreak, the IMPAACT network ran a series of Phase I clinical trials to evaluate the safety and immunogenicity of the H1N1 vaccine in HIV positive pregnant women and adolescent children. Since there is a significant amount of expertise in non-HIV infectious diseases within NIH and NIAID, the currently funded HIV/AIDS clinical trials networks could play a bigger role in this area in the future. With the understanding that each outbreak will have its own unique challenges, the networks and any sites that are located in areas affected by future outbreaks should be ready and available the need arises. NIAID will continue to use the pay-as-you-go process of renting facilities such as network labs or data management systems.
Is the malaria vaccine in HIV infected/at risk populations a priority?
While malaria has not been a high priority for the HIV/AIDS clinical trials networks, it is something to consider in the future depending on the efficacy results of several Phase III malaria vaccine studies. The networks currently do not have a site footprint in areas endemic with malaria. This would be a good example of where the networks could use a pay-as-you-go model with DMID sites or other sites to perform such trials.
Will non-HIV research be integrated into NIAID clinical sites, such as the antibiotic resistance research group from DMID?
There is great promise in using the HIV/AIDS clinical trial networks to conduct research that addresses infectious disease issues. As the research agenda develops, DMID and DAIDS will discuss site location, capacity, and availability for future non-HIV studies. For example, it may be possible for the VRC to use the network sites on a pay-as-you-go model for studies involving Zika and other infectious diseases.
How do you see funding across the three scientific areas (vaccines, non-vaccine prevention, and therapeutics) evolving compared with current funding levels?
Availability of NIH funding will largely depend on scientific priority and the compelling nature of the research agenda. Funding levels change as new, costly, large Phase IIb and III trials launch. NIAID is working on a dynamic pricing model to assist with allocating funds to high-priority scientific opportunities.
Will NIAID have a full agenda, or will each of the individual research areas—vaccines, non-vaccine prevention, and therapeutics—continue to have their own agendas that are developed independently?
NIAID encourages collaboration and sharing of data and information across the HIV/AIDS research field. There have been many instances of overlap on product development and evaluation. For example, broadly neutralizing antibodies (bNAbs) are being evaluated for prevention, direct intervention, and treatment. If we are using a product in three different spheres of research, we need to find a way to more easily evaluate the aggregate safety data without having to go into three different data streams. For this to occur, we need better collaboration, not forced integration.
You seem to suggest that non-infectious co-morbidities will need partnerships in order to be studied. Does this mean NIAID will need funding from other institutes?
HIV/AIDS research is supported across many NIH institutes. NIAID does not always have the expertise needed to address specific co-morbidities. Other institutes can bring the expertise and funding needed for a particular study, such as in the previously mentioned REPRIEVE trial. In these situations, NIAID can provide the network infrastructure, oversight of clinical trials, monitoring pharmacy, and related functions.
Many of the initiatives described require the development of drugs and vaccines that can only be manufactured and distributed by the pharmaceutical industry. How does DAIDS intend to partner with industry to assure development and approval of the most promising interventions?
Partnerships among NIAID, the clinical trials networks, and industry are incredibly important to ensure that we continue to see progress in developing vaccines and therapeutic and prevention interventions. NIAID relies on the intellectual power, creativity, and problem solving capacities of the network leadership, investigators, and committee members to obtain and evaluate the best products available from industry. One example is injectable cabotegravir, which is now being evaluated in HPTN 083 in collaboration with ViiV Healthcare. Also, a number of HIV vaccines being manufactured by industry partners are being developed and evaluated in HIV Vaccine Trials Network (HVTN) studies. Moving forward, the key is to lay the groundwork needed at the concept level so industry will be more willing to participate.
How will NHLBI, NIDDK, and other NIH Institutes be engaged for collaborations going forward? Will they participate in the RFA, or will this need to be negotiated by the network?
NIAID will be using the model previously employed to involve other institutes: leveraging the NIH Office of AIDS Research (OAR) to identify institutes willing to tackle strategic challenges that overlap with their interests. Since NIAID is not the expert on non-HIV issues such as diabetes or cardiovascular disease, we rely on OAR to help us find partners within NIH. Several sponsored meetings already have led to the formation of some partnerships. As research agendas develop and focus on specific areas, these collaborations will be critical for the next steps.
Will there be an evolving relationship with the National Institute of Child Health and Human Development (NICHD) Adolescent Trials Network (ATN) as a partnership or something more integrated?
This is an area that is still being discussed at NIAID. The new ATN launched approximately 14 months ago, and the prevention trials network has been partnering with them through the ATN sites. Given that ATN is primarily domestic, there may be very strong reasons for continuing our partnership with them as we advance toward 2020 and beyond.
Do you intend to maintain the current leadership structure for Clinical Trial Units (CTU) and Clinical Research Sites (CRS), e.g., a CTU Principal Investigator (PI)/Co-PIs and a single PI for each CRS? Or would you consider alternative leadership structures, e.g. separate PI's for each supported Network?
We are satisfied with the current leadership structure for the networks, so we would not be in favor of supported principal investigators for each separate network.
With the massive increase in opioid epidemic, are there specific instructions for targeting this population?
As we consider the interaction between the opioid epidemic and the HIV epidemic, we must remember that the networks’ primary focus should be addressing the HIV/AIDS epidemic. The two may be inter-related. However, before we get involved in research to prevent HIV in the context of an opioid epidemic, we must be selective and focus on the relevant research question. What question should we answer related to the opioid epidemic? What questions have we already answered? For example, we know needle exchange works effectively, but its use may not be allowed as primary tool because of local, state, and federal laws.
You discussed target populations for HIV prevention but I'm wondering about whether you have considered targeting populations with emergent HIV epidemics such as U.S. rural populations with prevalent intravenous drug use.
We have discussed the concept of working with rural populations and how our network structure would need to adapt. We are very open to taking feedback on this topic, but have yet to hear a strategy to be able to efficiently and effectively reach the rural communities. There is already a shortage of doctors in the rural communities and there are some questions that need to be addressed, including access to the populations, gaining trust in these communities, creating community desire for this type of research, as well as the logistics of effectively conducting research in these areas. This is a great opportunity for the scientific and lay communities to work together and further advance the public health of the United States.
What are your thoughts about merging or continuing to separate treatment and prevention networks given that the biomedical approaches for both may be converging in the form of long-acting antiretroviral agents?
We are pleased with the current model for the Antibody Mediated Prevention (AMP) trials that have involved both the HIV Prevention Trials Network (HPTN) and HIV Vaccine Trials Network (HVTN). In this scenario, the broadly neutralizing antibody VRC01 holds importance for both prevention and vaccines and thus the two networks worked together to co-sponsor and conduct the study in an integrated way where both fields benefit. As we move forward the networks will need to seek additional areas where collaboration and cooperation can occur. So, rather than merge networks, we would like them to collaborate and pool their resources and brain power to achieve the best possible outcome for research design and analysis. NIAID wants to see more of an integration of activities and collaborations, and will place great emphasis on this moving forward.
How will the single Investigational Review Board (IRB) policy impact the reshaping of the Networks?
The single IRB policy remains an open area of discussion at NIAID. We are continuing to evaluate this further and discuss options. It is important to keep in mind that the single IRB policy applies to domestic studies. However, once we move into collaborations of both domestic and international studies, the rules for single IRBs do not apply. We are working through these changes and the logistical impact that may occur when the networks start in 2020.
Do you envision a standard data-management platform for all sites and networks, including non-HIV networks?
NIAID has taken some steps in this direction. We have started to require the Statistical and Data Management Centers to produce Clinical Data Interchange Standards Consortium-compatible datasets, and part of this effort involves the implementation of a platform called Medidata Rave. We will evaluate and consider whether additional standardization will improve overall interoperability.
Would results as expected, or even negative results, from P5 vaccine trials help inform our HIV vaccine research agenda?
All study results will help inform the future research agenda. For example, the results of the ongoing HVTN 702 trial, which is currently evaluating the safety and efficacy of the RV144-modified vaccine regimen, will impact any additional studies planned in 2020 and beyond. Many of the current studies will have results before 2020, and the research agenda, particularly with regard to HIV cure, TB prevention, and HIV vaccines and prevention, must have a degree of flexibility to account for these results.
Can you discuss the need for an HIV vaccine phase 1-2 program in the next cycle?
As we continue to make advancements in HIV vaccine research, we anticipate a continued need for early phase vaccine studies, especially when current trials involving broadly neutralizing monoclonal antibodies are completed. It is essential that we underpin our work with a strong, highly functional and innovative phase 1-2 HIV vaccine research program.
Can you expand a bit on the role of the existing NIH HIV/AIDS clinical trials networks in research on non-HIV disorders?
The NIH HIV/AIDS clinical trials networks play an important role in addressing non-HIV co-morbidities. A prime example is the NHLBI-NIAID REPRIEVE study, which is a large multicenter international study designed to evaluate whether statins can reduce the risk of major cardiovascular events. This study demonstrates how we utilize our research infrastructure and leadership to effectively address important co-morbidities.
You emphasized TB as an HIV co-infection. Will studies of TB be conducted only in co-infected people, or will studies in TB mono-infected people also be pursued? What about viral hepatitis?
Based on the funding structure at NIAID, DAIDS is responsible for tackling co-infections such as TB. However, DAIDS is aware that data and results from studies involving HIV-TB co-infected people may also be relevant to TB mono-infected people. There are opportunities for collaboration with other parts of NIAID, including the Division of Microbiology and Infectious Diseases (DMID) and Division of Intramural Research, with the goal of having a more integrated approach to tackle diseases such as TB that affect mono-infected and co-infected populations. Viral hepatitis is another important co-infection that needs to be discussed and considered for the agenda. The possible strategy moving forward may be to focus on therapeutics and prevention of hepatitis B. Another area of particular interest is HIV-induced inflammation, and residual disease where inflammation is the underlying cause of the non-infectious co-morbidities.
Do we expect to see a different kind of association between HIV and TB programs, especially as related to forms of TB immunotherapy?
NIAID is moving towards an integrated approach for tackling TB. A process needs to be developed for setting a broader TB agenda that covers improved treatment, vaccine development, and potential immunotherapy.
It makes sense to move away from Hepatitis C (HCV) research; but what about Hepatitis B (HBV)? It seems likely that HBV 'cure' research will move forward in the next decade, and there are a lot of similar challenges in curing both HIV and HBV.
We agree that Hepatitis B is as an important area of emphasis for our networks moving forward, and we will keep this in mind as we refine the scientific agenda.
Regarding implementation science research, is this a priority for NIH more broadly or specifically for the Networks scientific agendas?
NIH, particularly National Institute on Drug Abuse (NIDA) and National Institute of Mental Health (NIMH), are engaged in implementation science research. NIAID has and will continue to support implementation science projects where we have appropriate partnerships, such as with health departments, Centers for Disease Control and Prevention (CDC), and President's Emergency Plan for AIDS Relief (PEPFAR).
How will the Martin Delaney Collaboratory clinical trials relate to the NIH Therapeutic network? Will they be done at separate sites?
The research conducted by the Delaney Collaboratories and the AIDS Clinical Trials Group (ACTG) network can be described as different phases of research. Further, there may be a need for the ACTG to become more involved in the early phase studies. When there is a test of concept or an idea that needs to move beyond a small pilot to a multicenter trial, the networks would need to be involved.
With a growing recognition that no single interaction may be effective (besides ART), is there a strategy for encouraging a combinatorial approach for clinical trials?
The ultimate goal is to develop a combinational strategy with proven interventions. For Pre-exposure prophylaxis (PrEP) and vaccines for example, we need to understand how to integrate those together and how they could be synergistic. This would require crossnetwork interactions as well and partnering with groups like PEPFAR that would be interested in the same outcome.
The presentation stressed three networks but the Messages from NIAID indicated potential fusion of ALL prevention in one network. Where does this idea stand?
We posted a blog earlier this year discussing our initial thoughts on the scientific research priorities and network structure. Based on the feedback we have received regarding the concept of a single prevention network, we determined that the differences in traditional HIV prevention research and HIV vaccine research, particularly at the early stages, are simply too divergent to allow for an effective merger of those activities. There is a level of integration and sharing that can still occur, especially with phase 2b and larger studies. Thus, rather than merging, we are promoting collaboration for large phase studies.
The current planning clearly focuses on systemic HIV prevention. But NIH has invested and continues to invest in topical agents for HIV prevention. What can we expect for this topic in the network renewals? If this approach will not be part of the renewals what mechanism, do you intend to support this type of research and how much will it be prioritized?
Moving forward, we need to identify innovative strategies that will deliver better prevention and treatment. NIAID has been a strong supporter of topical agents for HIV prevention. While studies have shown that a vaginal ring can be partially effective, data from the ASPIRE study also found that it was not effective for women under 25 years old. When designing a prevention strategy for women, we need to consider whether it will be acceptable or used by young women and whether there is something about the biology or sexual practices of young women that prevents these types of products from being effective. This raises the challenge of adherence and how to design products that make it easier to use. We need to have a prevention program that focuses on protecting the person regardless of exposure, and takes into account the realities of how people have sex and protect themselves. If we are successful, we will be able to provide the best products and methods for preventing HIV infection. Should topical tools emerge that have a likelihood of overcoming these challenges and being safe, effective and desirable, they would be considered for clinical research investment.
How many CTUs do you anticipate you will need?
We do not know how many CTUs we will need but we anticipate that it will be fewer than what we currently have. These needs will be spelled out at the upcoming advisory committee meeting.
Will there be an effort to look at sites that can be productive in multiple areas of research and to get the networks to work together to avoid similar needs being completed in different ways as can be sometime seen with prevention and treatment with long acting agents?
We plan to continue our efforts to promote harmonization across networks, including identifying clinical sites that can participate in multidisciplinary research (i.e., pluripotent sites). This process will need to account for the three scientific areas of emphasis and the special populations that we need to address. Ultimately, the goal is harmonization between the leadership groups, so that protocol training and other challenges that make it difficult for sites to work across multiple leadership groups are addressed in the future. If we focus on harmonization improvements across the areas of emphasis, it will make it easier for sites to work at completing the wide range of activities they can achieve.
With intent to decrease numbers of sites, are you discouraging application of new sites, even if they have excellent access to target populations now currently not targeted (e.g. rural)?
We are not discouraging anyone from applying. The key point to remember is that as we move towards the future, we need to focus on newer populations that are critical to reach. We are also open to ideas on how to effectively reach previously untapped populations in specific regions of the U.S. At the same time, we also need to manage expectations as we refine the agenda and to ensure that our areas of emphasis stay focused on the highest priority questions. This process will naturally address the number of sites and which will participate.